This invention relates to a group of benzo thiadiazine derivatives which inhibit matrix metalloproteinase enzymes, and thus are useful for treating diseases resulting from tissue breakdown, such as heart disease, multiple sclerosis, arthritis, atherosclerosis, and osteoporosis.
Matrix metalloproteinases (sometimes referred to as MMPs) are naturally occurring enzymes found in most mammals. Over-expression and activation of MMPs or an imbalance between MMPs and inhibitors of MMPs have been suggested as factors in the pathogenesis of diseases characterized by the breakdown of extracellular matrix or connective tissues.
Stromelysin-1 and gelatinase A are members of the matrix metalloproteinases (MMP) family. Other members include fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8), gelatinase B (92 kDa gelatinase) (MMP-9), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), matrilysin (MMP-7), collagenase 3 (MMP-13), TNF-alpha converting enzyme (TACE), and other newly discovered membrane-associated matrix metalloproteinases (Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M., Nature, 1994;370:61-65). These enzymes have been implicated with a number of diseases which result from breakdown of connective tissue, including such diseases as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation which leads to restenosis and ischemic heart failure, and tumor metastasis. A method for preventing and treating these and other diseases is now recognized to be by inhibiting metalloproteinase enzymes, thereby curtailing and/or eliminating the breakdown of connective tissues that results in the disease states.
The catalytic zinc in matrix metalloproteinases is typically the focal point for inhibitor design. The modification of substrates by introducing zinc chelating groups has generated potent inhibitors such as peptide hydroxamates and thiol-containing peptides. Peptide hydroxamates and the natural endogenous inhibitors of MMPs (TIMPs) have been used successfully to treat animal models of cancer and inflammation. MMP inhibitors have also been used to prevent and treat congestive heart failure and other cardiovascular diseases, U.S. Pat. No. 5,948,780.
A major limitation on the use of currently known MMP inhibitors is their lack of specificity for any particular enzyme. Recent data has established that specific MMP enzymes are associated with some diseases, with no effect on others. The MMPs are generally categorized based on their substrate specificity, and indeed the collagenase subfamily of MMP-1, MMP-8, and MMP-13 selectively cleave native interstitial collagens, and thus are associated only with diseases linked to such interstitial collagen tissue. This is evidenced by the recent discovery that MMP-13 alone is over expressed in breast carcinoma, while MMP-1 alone is over expressed in papillary carcinoma (see Chen et al., J. Am. Chem. Soc., 2000;122:9648-9654).
There appears to be few selective inhibitors of MMP-13 reported. A compound named WAY-170523 has been reported by Chen et al., supra., 2000, and a few other compounds are reported in PCT international application publication number WO 01/63244 A1, as allegedly selective inhibitors of MMP-13. Further, U.S. Pat. No. 6,008,243 discloses inhibitors of MMP-13. However, no selective or nonselective inhibitor of MMP-13 has been approved and marketed for the treatment of any disease in any mammal. Accordingly, the need continues to find new low molecular weight compounds that are potent and selective MMP inhibitors, and that have an acceptable therapeutic index of toxicity/potency to make them amenable for use clinically in the prevention and treatment of the associated disease states. An object of this invention is to provide a group of selective MMP-13 inhibitor compounds characterized as being benzo thiadiazines.
This invention provides a group of benzo thiadiazine compounds that are inhibitors of matrix metalloproteinase enzymes, and especially MMP-13. The invention is more particularly directed to compounds defined by Formula I 
or a pharmaceutically acceptable salt thereof, wherein:
n is 0, 1,or 2;
X is O or NH;
R2 is H, C1-C6 alkyl, or C1-C6 substituted alkyl;
R1 and R3 independently are H, acyl, substituted acyl, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C2-C6 alkynyl, C1 C6 substituted alkynyl, (CH2)m aryl, (CH2)m substituted aryl, (CH2)m heteroaryl, (CH2)m substituted heteroaryl, (CH2)m cycloalkyl, or (CH2)m substituted cycloalkyl; and
each m independently is an integer of from 0 to 6,
with the proviso that R3 is not (CH2)m biphenyl or (CH2)m substituted biphenyl.
Another invention embodiment are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R1 and R3 are not both selected from H or C1-C6 alkyl.
Another invention embodiment are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R3 is not acyl or substituted acyl when X is O.
Another invention embodiment are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein each m is 1.
Another invention embodiment are compounds of Formula II 
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and X are as defined above.
Another invention embodiment are compounds of Formulas I or II, or a pharmaceutically acceptable salt thereof, wherein R2 is H, alkyl or substituted alkyl, and R1 and R3 independently are (CH2)m phenyl, (CH2)m heteroaryl, (CH2)m cycloalkyl, C2-C6 alkenyl, or C2-C6 substituted alkenyl, wherein phenyl, heteroaryl, and cycloalkyl may be unsubstituted or substituted.
Another invention embodiment are compounds of Formulas I or II, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen or C1-C6 alkyl, and R1 and R3 independently are C1-C6 substituted alkyl, wherein at least one substituent is an aryl group such as phenyl or substituted phenyl.
Another invention embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, selected from:
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid benzyl ester;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-b enzo[1,2,4]thiadiazine-7-carboxylic acid benzylamide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid (1H-indol-5-ylmethyl)-amide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-(2-tert-butylsulfamoyl-ethyl)-benzylamide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid (1H-indol-2-ylmethyl)-amide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-(2-sulfamoyl-ethyl)-benzylamide;
2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid benzylamide;
4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,3,4]thiadiazin-2-ylmethyl]-benzoic acid tert-butyl ester;
4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid;
2-(4-Carbamoyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid 4-fluoro-benzylamide;
4-Methyl-2-(4-nitro-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-Methyl-2-(4-methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-Methyl-2-[4-(morpholine-4-sulfonyl)-benzyl]-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-[7-(4-Fluoro-benzylcarbamoyl)4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid methyl ester;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide;
4-Methyl-2-naphthalen-2-ylmethyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-Biphenyl-4-ylmethyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid (2,1,3-benzothiadiazol-5-ylmethyl)-amide;
4-[7-(4-Fluoro-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid;
4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid 2-dimethylamino-ethyl ester hydrochloride;
4-Methyl-1,1,3-trioxo-2-[4-(piperidine-1-carbonyl)-benzyl]-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-{4-[7-(4-Methoxy-benzylcarbamoyl)4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1xcex6-benzo[1,2,3,4]thiadiazin-2-ylmethyl]-benzoylamino}-3-methyl-butyric acid;
2-(4-Cyano-benzyl)4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
{4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1xcex6-benzo[1,2,3,4]thiadiazin-2-ylmethyl]-phenyl }-acetic acid;
4-[7-(3-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1xcex6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid;
4-Methyl-1,1,3-trioxo-2-[4-(2H-tetrazol-5-yl)-benzyl]-1,2,3,4-tetrahydro-1xcex6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-(4-Amino-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1xcex6-benzo[1,2,4]thiadiazine-7-carboxylic acid 3-methoxy-benzylamide;
4-Methyl-1,1,3-trioxo-2-pent-2-ynyl-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-Methyl-1,1,3-trioxo-2-(1-phenyl-ethyl)-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-(5-Cyano-pentyl)4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-(E)-But-2-enyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-Methyl-1,1,3-trioxo-2-(E)-pent-2-enyl-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-Methyl-2-(2-methyl-allyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-Methyl-2-(3-methyl-but-2-enyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-Methyl-1,1,3-trioxo-2-[2-(toluene-4-sulfonyl)-ethyl]-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-[3-(4-Fluoro-phenyl)-3-oxo-propyl]-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-Methyl-1,1,3-trioxo-2-{2-[(1-phenyl-methanoyl)-amino]-ethyl }-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-Benzo[1,2,5]oxadiazol-5-ylmethyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
{5-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,3,4]thiadiazin-2-ylmethyl]-isoxazol-3-yl}-carbamic acid methyl ester; and
4-Methyl-1,1,3-trioxo-2-thiazol-4-ylmethyl-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide.
Another invention embodiment is a compound selected from:
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 3-methoxy-benzylamide;
4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-(4-Methyl-1,1,3-trioxo-7-[(pyridin-4-ylmethyl)-carbamoyl]-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-(4-Methyl-1,1,3-trioxo-7-[(pyridin-3-ylmethyl)-carbamoyl]-3,4-dihydro-1H-1l6-benzo[1,2,3,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-[7-(3-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1 H-1l6-benzo[1,2,3,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-(4-Methyl-1,1,3-trioxo-7-[(pyridin-4-ylmethyl)-carbamoyl]-3,4-dihydro-1H-1l6-benzo[1,2,3,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-(4-Methyl-1,1,3-trioxo-7-[(pyridin-3-ylmethyl)-carbamoyl]-3,4-dihydro-1H-1l6-benzo[1,2,3,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,3,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-[7-(3-Methoxy-benzylcarbamoyl)4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
{4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl }-acetic acid tert-butyl ester;
{4-(4-Methyl-1,1,3-trioxo-7-[(pyridin-4-ylmethyl)-carbamoyl]-3,4-dihydro-1H-1l6-benzo[1,2,3,4]thiadiazin-2-ylmethyl)-phenyl }-acetic acid tert-butyl ester;
{4-(4-Methyl-1,1,3-trioxo-7-[(pyridin-3-ylmethyl)-carbamoyl]-3,4-dihydro-1H-1l6-benzo[1,2,3,4]thiadiazin-2-ylmethyl)-phenyl }-acetic acid tert-butyl ester;
{4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl }-acetic acid tert-butyl ester;
{4-[7-(3-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1-H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid tert-butyl ester;
{4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid;
{4-(4-Methyl-1,1,3-trioxo-7-[(pyridin-4-ylmethyl)-carbamoyl]-3,4-dihydro-1H-1l6-benzo[1,2,3,4]thiadiazin-2-ylmethyl)-phenyl }-acetic acid;
{4-(4-Methyl-1,1,3-trioxo-7-[(pyridin-3-ylmethyl)-carbamoyl]-3,4-dihydro-1H-1l6-benzo[1,2,3,4]thiadiazin-2-ylmethyl)-phenyl }-acetic acid;
{4-[7-(4-Methoxy-benzylcarbamoyl)4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,3,4]thiadiazin-2-ylmethyl)-phenyl }-acetic acid;
{4-[7-(3-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,3,4]thiadiazin-2-ylmethyl)-phenyl }-acetic acid;
2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid benzylamide;
2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide;
2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide;
2-(4-Methanesulfonyl-benzyl)4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-(4-Methanesulfonyl-benzyl)4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 3-methoxy-benzylamide;
4-Methyl-2-(4-methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid benzylamide;
4-Methyl-2-(4-methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide;
4-Methyl-2-(4-methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide;
4-Methyl-2-(4-methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-Methyl-2-(4-methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid 3-methoxy-benzylamide;
2-(4-Dimethylsulfamoyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid benzylamide;
2-(4-Dimethylsulfamoyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide;
2-(4-Dimethylsulfamoyl-benzyl)4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide;
2-(4-Dimethylsulfamoyl-benzyl)4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-(4-Dimethylsulfamoyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 3-methoxy-benzylamide;
2-Benzyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid benzylamide;
2-Benzyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide;
2-Benzyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide;
2-Benzyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-Benzyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid 3-methoxy-benzylamide;
4-(7-Benzylcarbamoyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-(1,1,3-Trioxo-7-[(pyridin-4-ylmethyl)-carbamoyl]-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-(1,1,3-Trioxo-7-[(pyridin-3-ylmethyl)-carbamoyl]-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-[7-(4-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1H-1l6 benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-[7-(3-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1H-116-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-(7-Benzylcarbamoyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-(1,1,3-Trioxo-7-[(pyridin-4-ylmethyl)-carbamoyl]-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-(1,1,3-Trioxo-7-[(pyridin-3-ylmethyl)-carbamoyl]-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-[7-(4-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-[7-(3-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
{4-(7-Benzylcarbamoyl-1,1,3-trioxo-3,4-dihydro-1H-1l6 benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid tert-butyl ester;
{4-(1,1,3-Trioxo-7-[(pyridin-4-ylmethyl)-car bamoyl]-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid tert-butyl ester;
{4-(1,1,3-Trioxo-7-[(pyridin-3-ylmethyl)-carbamoyl]-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid tert-butyl ester;
{4-[7-(4-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid tert-butyl ester;
{4-[7-(3-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid tert-butyl ester;
{4-(7-Benzylcarbamoyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl }-acetic acid;
{4-(1,1,3-Trioxo-7-[(pyridin-4-ylmethyl)-carbamoyl]-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid;
{4-(1,1,3-Trioxo-7-[(pyridin-3-ylmethyl)-carbamoyl]-3,4-dihydro-1H-116-benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid;
{4-[7-(4-Methoxy-benzylcarbamoyl) 1,1,3-trioxo-3,4-dihydro-1H-116-benzo[1,2,3,4]thiadiazin-2-ylmethyl)-phenyl }-acetic acid;
{4-[7-(3-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid;
2-(4-Methanesulfonyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid benzylamide;
2-(4-Methanesulfonyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide;
2-(4-Methanesulfonyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide;
2-(4-Methanesulfonyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-(4-Methanesulfonyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 3-methoxy-benzylamide;
2-(4-Methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid benzylamide;
2-(4-Methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide;
2-(4-Methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide;
2-(4-Methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,3,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-(4-Methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 3-methoxy-benzylamide;
2-(4-Dimethylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid benzylamide;
2-(4-Dimethylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide;
2-(4-Dimethylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide;
2-(4-Dimethylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; and
2-(4-Dimethylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 3-methoxy-benzylamide.
A further embodiment of this invention is use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease mediated by an MMP-13 enzyme.
Another invention embodiment is use of a compound of Formula II, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease mediated by an MMP-13 enzyme.
Another invention embodiment is use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
Another invention embodiment is use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of rheumatoid arthritis.
Another invention embodiment is use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of osteoarthritis.
Another invention embodiment is use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of heart failure.
A further embodiment of this invention is a pharmaceutical composition, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, excipient, or diluent.
Another invention embodiment is a pharmaceutical composition, comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.
Another embodiment of this invention is a method for inhibiting an MMP-13 enzyme in an animal, comprising administering to the animal an MMP-13 inhibiting amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
A further embodiment is a method for treating a disease mediated by an MMP-13 enzyme, comprising administering to a patient suffering from such a disease an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method for treating a cancer, comprising administering to a patient suffering from such a disease an anticancer effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method for treating breast carcinoma, comprising administering to a patient suffering from such a disease an anticancer effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method for treating a rheumatoid arthritis, comprising administering to a patient suffering from such a disease an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method for treating a osteoarthritis, comprising administering to a patient suffering from such a disease an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method for treating a heart failure, comprising administering to a patient suffering from such a disease an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method for treating a inflammation, comprising administering to a patient suffering from such a disease an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention is a process for preparing a compound of Formula I 
or a pharmaceutically acceptable salt thereof, wherein:
n is 0, 1, or 2;
X is O or NH;
R2 is H, C1-C6 alkyl, or C1-C6 substituted alkyl;
R1 and R3 independently are H, acyl, substituted acyl, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C2-C6 alkynyl, C1-C6 alkynyl, (CH2)m aryl, (CH2)m substituted aryl, (CH2)m heteroaryl, (CH2)m substituted heteroaryl, (CH2)m cycloalkyl, or (CH2)m substituted cycloalkyl; and
each m independently is an integer of from 0 to 6, with the proviso that R3 is not (CH2)m biphenyl or (CH2)m substituted biphenyl,
the process comprising the step of:
contacting a compound of Formula (A) 
wherein n, R1, and R2 are as defined above, and
L is CO2H, CO2M, C(xe2x95x90O)-halo, C(xe2x95x90O)xe2x80x94OR7, C(xe2x95x90O)NR8R9, C(xe2x95x90O)xe2x80x94C(halo)3, or Cxe2x89xa1N, wherein R7 is pentafluorophenyl, C(xe2x95x90O)R2, or S(O)R2, wherein R2 is as defined above;
R8 and R9 are taken together with the nitrogen atom to which they are attached to form imidazol-1-yl, phthalimid-1-yl, benzotriazol-1-yl, or tetrazol-1-yl; and M is an alkali earth metal cation or alkaline earth metal cation, with a solvent and a compound of Formula (B)
Dxe2x80x94R3xe2x80x83xe2x80x83(B) 
wherein R3 is as defined above and D is HO, H2N, MO, or MN(H), wherein M is as defined above, optionally in the presence of from 1 to 3 agents selected from:
a coupling agent, a tertiary organic amine, an acid catalyst, a base catalyst, an acid halide, and an acid anhydride.
Another invention embodiment is the invention process wherein n is 2.
Another invention embodiment is the invention process, wherein n is 2 and X is O.
Another invention embodiment is the invention process, wherein n is 2 and X is NH.
Another invention embodiment is the invention process, wherein R1 and R3 independently are (CH2)m aryl, (CH2)m substituted aryl, (CH2)m heteroaryl, (CH2)m substituted heteroaryl.
Another invention embodiment is any one of the above embodiments of the invention process wherein L is CO2H, CO2M, or C(xe2x95x90O)-halo.
The compounds provided by this invention are those defined by Formula I. In Formula I, R1 to R3 include xe2x80x9cC1-C6 alkylxe2x80x9d groups. These are straight and branched carbon chains having from 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, isopropyl, tert-butyl, neopentyl, and n-hexyl. The alkyl groups can be substituted if desired, for instance with groups such as hydroxy, alkoxy, amino, alkyl and dialkylamino, alkanoyl, acyl, halo, trifluoromethyl, carboxy, nitro, and cyano.
xe2x80x9cAlkenylxe2x80x9d means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl, and the like.
xe2x80x9cAlkynylxe2x80x9d means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one triple bond and includes ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like.
xe2x80x9cCycloalkylxe2x80x9d means a monocyclic or polycyclic hydrocarbyl group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbomyl, cyclohexyl, and cyclopentyl. Such groups can be substituted with groups such as hydroxy, keto, and the like. Also included are rings in which 1 to 3 heteroatoms replace carbons. Such groups are termed xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclylxe2x80x9d, which means a cycloalkyl group also bearing at least one heteroatom selected from O, S, or NR2, examples being oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, and morpholine.
xe2x80x9cAlkoxyxe2x80x9d refers to the alkyl groups mentioned above bound through oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like. In addition, alkoxy refers to polyethers such as xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94CH3, and the like. xe2x80x9cThioalkoxyxe2x80x9d is an alkoxy group wherein the 0 is replaced by an S.
xe2x80x9cAlkanoylxe2x80x9d groups are alkyl linked through a carbonyl, ie, C1xe2x80x94C5xe2x80x94C(O)xe2x80x94. Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl.
xe2x80x9cAcylxe2x80x9d means an R group that is a C1-C6 alkyl or aryl (Ar) group bonded through a carbonyl group, i.e., Rxe2x80x94C(O)xe2x80x94, wherein C1-C6 alkyl and aryl are as defined above and below, respectively. The phrase xe2x80x9csubstituted acylxe2x80x9d means an R group that is a substituted C1-C6 alkyl or a substituted aryl (substituted Ar) group bonded through a carbonyl group. For example, substituted acyl includes substituted alkanoyl, wherein the alkyl portion can be substituted by NR4R5 or a carboxylic or heterocyclic group. Typical acyl groups include acetyl, benzoyl, and the like. Typical substituted acyl groups include trifluoroacetyl, 4-carboxybenzoyl, and the like.
The alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted, preferably by 1 to 3 groups selected from NR4R5, phenyl, substituted phenyl, (CH2)mxe2x80x94C(O) phenyl, (CH2)m C(O) substituted phenyl, (CH2)mxe2x80x94S(O)0-2 phenyl, (CH2)m S(O)0-2 substituted phenyl, (CH2)mxe2x80x94C(O) heteroaryl, (CH2)m C(O) substituted heteroaryl, (CH2)mxe2x80x94S(O)0-2 heteroaryl, (CH2)mxe2x80x94S(O)0-2 substituted heteroaryl, (CH2)m cycloalkyl, heterocycle, thio C1-C6 alkyl, C1-C6 alkoxy, hydroxy, acyl, carboxy, alkanoyl, C1-C6 alkoxycarbonyl, halo, nitro, nitrile, cycloalkyl, and a 5-or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. xe2x80x9cSubstituted nitrogenxe2x80x9d means nitrogen bearing C1-C6 alkyl or (CH2)yPh where y is 1, 2, or 3. Perhalo and polyhalo substitution is also embraced.
R4 and R5 independently are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, acyl, (CH2)m aryl, (CH2)m heteroaryl, (CH2)m cycloalkyl, wherein these groups may be unsubstituted or substituted as described herein, or R4 and R5 are taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered ring containing carbon atoms, the nitrogen atom bearing R4 and R5, and optionally 1 or 2 heteroatoms selected from O, S, NH, and NR2, wherein R2 is as defined above, the ring optionally may be substituted with oxo (xe2x80x9cxe2x95x90Oxe2x80x9d) on a carbon atom.
Examples of NR4R5 groups include amino, methylamino, di-isopropylamino, acetyl amino, propionyl amino, 3-aminopropyl amino, 3-ethylaminobutyl amino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl amino, and 3-carboxypropionyl amino. R4 and R5 can be taken together with the nitrogen to which they are attached to form a ring having 3 to 7 carbon atoms and 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, and sulfur. Examples of such cyclic NR4R5 groups include pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, pyridinyl, piperidinyl, pyrazinyl, morpholinyl, and the like.
xe2x80x9cHaloxe2x80x9d includes fluoro, chloro, bromo, and iodo.
Examples of substituted alkyl groups include 2-aminoethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl, benzyl(Bn), 3-morpholinopropyl, piperazinylmethyl, pyridyl-4-methyl(Py-4-me), 3-(pyridyl-4-thio)propyl, and 2-(4-methylpiperazinyl)ethyl.
Examples of substituted alkynyl groups include 2-methoxyethynyl, 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the like.
Typical substituted alkoxy groups include aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like.
Further, examples of substituted alkyl, alkenyl, and alkynyl groups include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl, and the like.
The terms xe2x80x9cArxe2x80x9d and xe2x80x9carylxe2x80x9d refer to unsubstituted and substituted aromatic groups. Heteroaryl groups have from 4 to 10 ring atoms, from 1 to 4 of which are independently selected from the group consisting of 0, S, and N. Preferred heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. Mono- and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl. Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 3,4-methylenedioxyphenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl, 4-thiopyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, morpholinyl, indolyl, benzotriazolyl, indazolyl, pyrrole, pyrazole, imidazole, thiazole, and the like.
Preferred Ar groups are phenyl or naphthyl, and phenyl or naphthyl substituted by 1, 2, or 3 groups independently selected from the group consisting of alkyl, alkoxy, thio, thioalkyl, thioalkoxy, (CH2)mN(R4)S(O)2(C1-C6 alkyl), (CH2)mS(O)2NR4R5, wherein R4, R5, and m are as defined above, S(O)2NR4R5, C(O)NR4R5, N(H)C(O)NR4R5, Oxe2x80x94C(O)NR4R5, halo, hydroxy, xe2x80x94COOR6, trifluoromethyl, nitro, amino of the formula xe2x80x94NR4R5, C(O)NR4R5, S(O)C1-C6 alkyl, S(O)2C1-C6 alkyl, 5-membered heteroaryl, N(R5)C(O)O(C1-C6 alkyl), and T(CH2)pQR4 or T(CH2)pCO2R4, wherein p is 1 to 6, T is O, S, SO, SO2, NR4, N(O)R4, NR4R6Y, or CR4R5, Q is O, S, SO, SO2, NR4, N(O)R5, or NR5R6Y, wherein R4 and R5 are as described above, Y is a counter ion such as halo, R6 is H, C1-C6 alkyl, or substituted C1-C6 alkyl, for example, methyl, trichloroethyl, diphenylmethyl, and the like. The alkyl and alkoxy groups can be substituted as defined above. For example, typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl. Examples of substituted phenyl are 3-methoxyphenyl, 2,6-dichlorophenyl, 3-nitrophenyl, 4-dimethylaminophenyl, and biphenyl. Examples of quaternary ammonium groups defined by NR4R6Y are trimethylammonium chloride and triethylammonium bromide.
Heteroaryl groups may be substituted with up to 3 groups independently selected from the 1, 2, or 3 groups described above for substituted phenyl.
The phrase xe2x80x9ctertiary organic aminexe2x80x9d means a trisubstituted nitrogen group wherein the 3 substituents are independently selected from C1-C12 alkyl, C3-C12 cycloalkyl, benzyl, or wherein two of the substituents are taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered, monocyclic heterocycle containing one nitrogen atom and carbon atoms, and the third substituent is selected from C1-C12 alkyl and benzyl, or wherein the three substituents are taken together with the nitrogen atom to which they are attached to form a 7- to 12-membered bicyclic heterocycle containing 1 or 2 nitrogen atoms and carbon atoms, and optionally a Cxe2x95x90N double bond when 2 nitrogen atoms are present. Illustrative examples of tertiary organic amine include triethylamine, diisopropylethylamine, benzyl diethylamino, dicyclohexylmethyl-amine, 1,8-diazabicycle[5.4.0]undec-7-ene (xe2x80x9cDBUxe2x80x9d), 1,4-diazabicyclo[2.2.2]octane (xe2x80x9cTEDxe2x80x9d), and 1,5-diazabicycle[4.3.0]non-5-ene.
The term xe2x80x9ccoupling agentxe2x80x9d includes any reagent, or any combination of two, three, or four reagents, conventionally used to promote coupling of a carboxylic acid, or a pharmaceutically acceptable salt thereof, with an alcohol or an amine to yield a carboxylic ester or carboxylic amide, respectively. The coupling agents are described in Reagents for Organic Synthesis, by Fieser and Fieser, John Wiley and Sons, Inc., New York, 2000; Comprehensive Organic Transformations, by Richard C. Larock, VCH Publishers, Inc., New York, 1989; the series Compendium of Organic Synthetic Methods (1989) by Wiley-Interscience; and the text Advanced Organic Chemistry, 5th edition, by Jerry March, Wiley-Interscience, New York (2001). Illustrative examples of coupling agents include N,Nxe2x80x2-carbonyldiimidazole (xe2x80x9cCDIxe2x80x9d), N, Nxe2x80x2-dicyclohexylcarbodiimide (xe2x80x9cDCCxe2x80x9d), triphenylphosphine with diethylazodicarboxylate, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (xe2x80x9cBOP-Clxe2x80x9d), POCl3, Ti(Cl)4, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (xe2x80x9cEDACxe2x80x9d).
The phrase xe2x80x9cacid catalystxe2x80x9d means any protic or Lewis acid that is conventionally used to catalyze coupling of a carboxylic acid, or a pharmaceutically acceptable salt thereof, a nitrile, carboxylic ester, carboxylic amide, carboxylic acid halide, or carboxylic acid anhydride with an alcohol or an amine to yield a carboxylic ester or carboxylic amide, respectively. The acid catalysts are described in Reagents for Organic Synthesis, by Fieser and Fieser, John Wiley and Sons, Inc., New York, 2000; Comprehensive Organic Transformations, by Richard C. Larock, VCH Publishers, Inc., New York, 1989; the series Compendium of Organic Synthetic Methods (1989) by Wiley-Interscience; and the text Advanced Organic Chemistry, 5th edition, by Jerry March, Wiley-Interscience, New York (2001). Illustrative examples include anhydrous hydrogen chloride, hydrochloric acid, hydrogen bromide in acetic acid, zinc chloride, titanium tetrachloride, acetic acid, trifluoroacetic acid, phenol, sulfuric acid, methanesulfonic acid, magnesium sulfate, Amberlyst-15 resin, silica gel, and the like.
It should be appreciated that a nitrile may be contacted with an alcohol or an amine in the presence of an acid catalyst, and the resulting intermediate imidate or amidine, respectively, may be contacted with water to yield the carboxylic ester or carboxylic amide, respectively.
The phrase xe2x80x9cbase catalystxe2x80x9d means any base that is conventionally used to catalyze coupling of a carboxylic acid, or a pharmaceutically acceptable salt thereof, carboxylic ester, carboxylic amide, carboxylic acid halide, or carboxylic acid anhydride with an alcohol or an amine to yield a carboxylic ester or carboxylic amide, respectively. The base catalysts are described in Reagents for Organic Synthesis, by Fieser and Fieser, John Wiley and Sons, Inc., New York, 2000; Comprehensive Organic Transformations, by Richard C. Larock, VCH Publishers, Inc., New York, 1989; the series Compendium of Organic Synthetic Methods (1989) by Wiley-Interscience; and the text Advanced Organic Chemistry, 5th edition, by Jerry March, Wiley-Interscience, New York (2001). Illustrative examples include sodium hydroxide, sodium hydride, potassium tert-butoxide, a tertiary organic amine, titanium tetraisopropoxide, sodium methoxide, sodium acetate, sodium bicarbonate, potassium carbonate, basic alumina, and the like.
The phrase xe2x80x9cacid halidexe2x80x9d means any carboxylic acid halide or sulfonic acid halide that is conventionally used to catalyze coupling of a carboxylic acid, or a pharmaceutically acceptable salt thereof, with an alcohol or an amine to yield a carboxylic ester or carboxylic amide, respectively. The acid halides are described in Reagents for Organic Synthesis, by Fieser and Fieser, John Wiley and Sons, Inc., New York, 2000; Comprehensive Organic Transformations, by Richard C. Larock, VCH Publishers, Inc., New York, 1989; the series Compendium of Organic Synthetic Methods (1989) by Wiley-Interscience; and the text Advanced Organic Chemistry, 5th edition, by Jerry March, Wiley-Interscience, New York (2001). Illustrative examples include acetyl chloride, trifluoromethanesulfonyl chloride, 2,2-dimethylacetyl bromide, para-toluenesulfonyl chloride, pentafluoro-benzoyl chloride, and the like.
The phrase xe2x80x9cacid anhydridexe2x80x9d means any carboxylic acid anhydride or sulfonic acid anhydride that is conventionally used to catalyze coupling of a carboxylic acid, or a pharmaceutically acceptable salt thereof, with an alcohol or an amine to yield a carboxylic ester or carboxylic amide, respectively. The acid anhydrides are described in Reagents for Organic Synthesis, by Fieser and Fieser, John Wiley and Sons, Inc., New York, 2000; Comprehensive Organic Transformations, by Richard C. Larock, VCH Publishers, Inc., New York, 1989; the series Compendium of Organic Synthetic Methods (1989) by Wiley-Interscience; and the text Advanced Organic Chemistry, 5th edition, by Jerry March, Wiley-Interscience, New York (2001). Illustrative examples include acetic anhydride, trifluoroacetic anhydride, trifluoromethanesulfonic acid anhydride, pentafluoro-benzoic anhydride, mixed anhydrides like trifluoroacetyloxycarbonylmethyl, and the like.
The term xe2x80x9chalidexe2x80x9d includes fluoride, chloride, bromide, and iodide.
The phrase xe2x80x9ccoupling catalystxe2x80x9d means any metal catalyst, preferably a transition metal catalyst, that is conventionally used to catalyze coupling of an aryl halide, aryl trifluoromethanesulfonate, heteroaryl halide, or heteroaryl trifluoromethanesulfonate, or activated derivatives thereof, including arylboronic acids, heteroarylboronic acids, aryl stannanes, heteroarylstannanes, aryl magnesium halides, heteroaryl magnesium halides, aryl lithiums, or heteroaryl lithiums, with an terminal alkyne to yield an arylalkyne or heteroarylalkyne. The coupling catalysts are described in Reagents for Organic Synthesis, by Fieser and Fieser, John Wiley and Sons, Inc., New York, 2000; Comprehensive Organic Transformations, by Richard C. Larock, VCH Publishers, Inc., New York, 1989; the series Compendium of Organic Synthetic Methods (1989) by Wiley-Interscience; and the text Advanced Organic Chemistry, 5th edition, by Jerry March, Wiley-Interscience, New York (2001). Illustrative examples of coupling catalysts include tetrakis(triphenylphosphine)palladium (0), palladium (II) chloride, palladium (II) acetate, iron (III) chloride, Heck reaction catalysts, Suzuki reaction catalysts, Stille reaction catalysts, and the like.
The group xe2x80x9cS(O)0-2xe2x80x9d means S, S(xe2x95x90O), or S(xe2x95x90O)2.
The descriptors xe2x80x9c1l6xe2x80x9d and xe2x80x9c1xcex6xe2x80x9d are synonymous.
The term xe2x80x9cpatientxe2x80x9d means a mammal. Preferred patients include humans, cats, dogs, cows, horses, pigs, and sheep.
The term xe2x80x9canimalxe2x80x9d means a mammal. Preferred animals are include humans, rats, mice, guinea pigs, rabbits, monkeys, cats, dogs, cows, horses, pigs, and sheep.
The phrases xe2x80x9ctherapeutically effective amountxe2x80x9d and xe2x80x9ceffective amountxe2x80x9d are synonymous unless otherwise indicated, and mean an amount of a compound of the present invention that is sufficient to improve the condition, disease, or disorder being treated. Determination of a therapeutically effective amount, as well as other factors related to effective administration of a compound of the present invention to a patient in need of treatment, including dosage forms, routes of administration, and frequency of dosing, may depend upon the particulars of the condition that is encountered, including the patient and condition being treated, the severity of the condition in a particular patient, the particular compound being employed, the particular route of administration being employed, the frequency of dosing, and the particular formulation being employed. Determination of a therapeutically effective treatment regimen for a patient is within the level of ordinary skill in the medical or veterinarian arts. In clinical use, an effective amount may be the amount that is recommended by the U.S. Food and Drug Administration, or an equivalent foreign agency.
The phrase xe2x80x9cadmixedxe2x80x9d or xe2x80x9cin admixturexe2x80x9d means the ingredients so mixed comprise either a heterogeneous or homogeneous mixture. Preferred is a homogeneous mixture.
The phrases xe2x80x9cpharmaceutical preparationxe2x80x9d and xe2x80x9cpreparationxe2x80x9d are synonymous unless otherwise indicated, and include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Pharmaceutical preparations are fully described below.
The phrase xe2x80x9canticancer effective amountxe2x80x9d means an amount of invention compound, or a pharmaceutically acceptable salt thereof, sufficient to inhibit, halt, or cause regression of the cancer being treated in a particular patient or patient population. For example in humans or other mammals, an anticancer effective amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular cancer and patient being treated.
The phrase xe2x80x9cMMP-13 inhibiting amountxe2x80x9d means an amount of invention compound, or a pharmaceutically acceptable salt thereof, sufficient to inhibit an enzyme matrix metalloproteinase-13, including a truncated form thereof, including a catalytic domain thereof, in a particular animal or animal population. For example in a human or other mammal, an MMP-13 inhibiting amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular MMP-13 enzyme and patient being treated.
It should be appreciated that the matrix metalloproteinases include the following enzymes:
MMP-1, also known as interstitial collagenase, collagenase-1, or fibroblast-type collagenase;
MMP-2, also known as gelatinase A or 72 kDa Type IV collagenase;
MMP-3, also known as stromelysin or stromelysin-1;
MMP-7, also known as matrilysin or PUMP-1;
MMP-8, also known as collagenase-2, neutrophil collagenase, or polymorphonuclear-type (xe2x80x9cPMN-typexe2x80x9d) collagenase;
MMP-9, also known as gelatinase B or 92 kDa Type IV collagenase;
MMP-10, also known as stromelysin-2;
MMP-11, also known as stromelysin-3;
MMP-12, also known as metalloelastase;
MMP-13, also known as collagenase-3;
MMP-14, also known as membrane-type (xe2x80x9cMTxe2x80x9d) 1-MMP or MT1-MMP;
MMP-15, also known as MT2-MMP;
MMP-16, also known as MT3-MMP;
MMP-17, also known as MT4-MMP;
MMP-18; and
MMP-19.
Other MMPs are known, including MMP-26, which is also known as matrilysin-2.
One aspect of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, that is a selective inhibitor of the enzyme MMP-13. A selective inhibitor of MMP-13, as used in the present invention, is a compound that is xe2x89xa75 times more potent in vitro versus MMP-13 than versus at least one other matrix metalloproteinase enzyme such as, for example, MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, or MMP-14, or versus tumor necrosis factor alpha convertase (xe2x80x9cTACExe2x80x9d). A preferred aspect of the present invention is a compound that is a selective inhibitor of MMP-13 versus MMP-1.
Another aspect of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, that is a selective inhibitor of MMP-13 versus 2, 3, 4, 5, 6, or 7 other MMP enzymes, or versus TACE and 1, 2, 3, 4, 5, 6, or 7 other MMP enzymes. O
Another aspect of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, that is xe2x89xa710 times, xe2x89xa720 times, xe2x89xa750 times, xe2x89xa7100 times, or xe2x89xa71000 times more potent versus MMP-13 than versus at least one of any other MMP enzyme or TACE.
It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration, is within the level of ordinary skill in the pharmaceutical and medical arts, and is described below.
The term xe2x80x9cIC50xe2x80x9d means the concentration of test compound required to inhibit activity of a biological target, such as a receptor or enzyme, by 50%.
The phrase xe2x80x9ccatalytic domainxe2x80x9d means the domain containing a catalytic zinc cation of the MMP enzyme, wherein the MMP enzyme contains 2 or more domains. A catalytic domain includes truncated forms thereof that retain at least some of the catalytic activity of MMP-13 or MMP-13CD. For example, the collagenases, of which MMP-13 is a member, have been reported to contain a signal peptide domain, a propeptide domain, a catalytic domain, and a hemopexin-like domain (Ye Qi-Zhuang, Hupe D., Johnson L., Current Medicinal Chemistry, 1996;3:407-418).
The phrase xe2x80x9ca method for inhibiting MMP-13xe2x80x9d includes methods of inhibiting full length MMP-13, truncated forms thereof that retain catalytic activity, including forms that contain the catalytic domain of MMP-13, as well as the catalytic domain of MMP-13 alone, and truncated forms of the catalytic domain of MMP-13 that retain at least some catalytic activity.
It should be appreciated that it has been shown previously (Ye Qi-Zhuang, et al., 1996, supra) that inhibitor activity against a catalytic domain of an MMP is predictive of the inhibitor activity against the respective full-length enzyme.
The compounds to be used in the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Some of the invention compounds may have one or more chiral centers, and as such can exist as individual enantiomers and mixtures. This invention contemplates all racemic mixtures, pure enantiomers, as well as geometric and positional isomers.
The compounds of Formulas I and II are capable of further forming both pharmaceutically acceptable salts, including but not limited to acid addition and/or base salts, solvates, and N-oxides of a compound of Formulas I and II. This invention also provides pharmaceutical formulations comprising a compound of Formulas I and II together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. All of these forms can be used in the method of the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of Formulas I and II include salts derived form inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorus, and the like, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like; see, for example, Berge et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. of Pharmaceutical Science, 1977;66:1-19.
The acid addition salts of the basic compounds are prepared by contacting the free-base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free-base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free-base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
Pharmaceutically acceptable base addition salts (for example when carboxylic acid groups are present) are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine; see, for example, Berge et al., supra.
The base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
The compounds of the present invention can be formulated and administered in a wide variety of oral and parenteral dosage forms, including parenteral, oral, transdermal, and rectal administration. All that is required is that an MMP inhibitor be administered to a mammal suffering from a disease in an effective amount, which is that amount required to cause an improvement in the disease and/or the symptoms associated with such disease. It will be recognized by those skilled in the art that the dosage forms provided herein may comprise as the active component, a compound of Formula I or a corresponding pharmaceutically acceptable salt or solvate of a compound of Formula I, admixed with any conventional excipient, diluent, or carrier.
A compound of Formula I, or a pharmaceutically acceptable salt thereof, may be prepared by one of ordinary skill in the art of organic chemistry by procedures found in the chemical literature such as, for example, Reagents for Organic Synthesis, by Fieser and Fieser, John Wiley and Sons, Inc., New York, 2000; Comprehensive Organic Transformations, by Richard C. Larock, VCH Publishers, Inc., New York, 1989; the series Compendium of Organic Synthetic Methods (1989) by Wiley-Interscience; the text Advanced Organic Chemistry, 5th edition, by Jerry March, Wiley-Interscience, New York (2001); or the Handbook of Heterocyclic Chemistry, by Alan R. Katritzky, Pergamon Press Ltd., London, (1985), to name a few. Alternatively, a skilled artisan may find methods useful for preparing the invention compounds in the chemical literature by searching widely available databases such as, for example, those available from the Chemical Abstracts Service, Columbus, Ohio, or MDL Information Systems GmbH (formerly Beilstein Information Systems GmbH), Frankfurt, Germany.
Preparations of the compounds of the present invention may use starting materials, reagents, solvents, and catalysts that may be purchased from commercial sources or they may be readily prepared by adapting procedures in the references or resources cited above. Commercial sources of starting materials, reagents, solvents, and catalysts useful in preparing invention compounds include, for example, The Aldrich Chemical Company, and other subsidiaries of Sigma-Aldrich Corporation, St. Louis, Mo., BACHEM, BACHEM A.G., Switzerland, or Lancaster Synthesis Ltd., United Kingdom.
Reagents for Organic Synthesis, by Fieser and Fieser, John Wiley and Sons, Inc., New York, 2000; Comprehensive Organic Transformations, by Richard C. Larock, VCH Publishers, Inc., New York, 1989; the series Compendium of Organic Synthetic Methods (1989) by Wiley-Interscience; the text Advanced Organic Chemistry, 5th edition, by Jerry March, Wiley-Interscience, New York (2001); and the Handbook of Heterocyclic Chemistry, by Alan R. Katritzky, Pergamon Press Ltd., London, (1985) are hereby incorporated by reference.
The invention compounds are prepared by methods well-known to those skilled in the art of organic chemistry. The compounds of Formula I are prepared utilizing commercially available starting materials, or reactants that are readily prepared by standard organic synthetic techniques. A typical synthesis of the invention compounds of Formula I is shown in Scheme 1 below. The first step in Scheme 1 comprises reacting a substituted (R2) anthranilate of formula (A) with N-chlorosulfonyl isocyanate (CSI) followed by an appropriate Lewis acid such as aluminum trichloride in the manner described by Girared Y et al., (J. Chem. Soc. Perkins I, 1979:1043-1047). The resulting 1,2,4-benzothiadiazone carboxylate (B) can then be alkylated in the 3 position to give the compound (C) (for example by reaction with a common alkylating agent such as an alkyl halide, generally in the presence of a base such as triethylamine or pyridine). Simple hydrolysis of the ester under standard conditions (eg, alkaline conditions) affords the carboxylic acid (D). This acid can then be further reacted with alcohols or amines to provide the desired ester or carboxylic amide (E) using standard coupling conditions known to those skilled in the art (such as 1,3-dicyclohexylcarbodiimide (DCC) activation, in situ acid halide formation, 1,1-carbonyldiimidazole (CDI) activation, etc.). The invention compounds can be isolated and purified by standard methods such as crystallization (from solvents such as alcohols, alkyl esters, haloalkanes, alkanes) and chromatography over solid supports such as silica gel (eluting with solvents such as dichloromethane, ethyl acetate, methanol). Optically active compounds can be isolated by standard methods, for example fractional crystallization, chiral synthesis, and classical resolution. 
An alternative synthesis of the benzothiadiazines of the invention is given in Scheme 2. In this case, a substituted (R2) anthranilate of formula (A) is reacted with excess chlorosulfonic acid to give the sulfonyl chloride (F). This sulfonyl chloride is readily converted to the corresponding sulfonamide (G) by reaction with saturated ammonium hydroxide or liquid ammonia. Reaction of this sulfonamide with urea (or a similar Cxe2x95x90O synthon such as phosgene or triphosgene) affords the desired 1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,2,4]thiadiazine ring system (B) which can be further elaborated to the compounds of the present invention as demonstrated in Scheme 1. 
During the synthesis of some of the invention compounds, it may be desirable to protect reactive functional groups such as hydroxy, amino, and carboxylic groups, so as to avoid unwanted side reactions. The use of protecting groups in synthetic organic chemistry is well established and is fully described by Greene and Wuts in xe2x80x9cProtecting Groups in Organic Synthesisxe2x80x9d (John Wiley and Son Press, 3rd ed). Examples of common amino protecting groups include acyl groups such as formyl and acetyl, and arylalkyl groups such as benzyl. Typical hydroxy protecting groups include ether forming groups such as methyl and ethyl, and acyl groups such as acetyl and tert-butoxycarbonyl (tBOC). Carboxylic acids generally are protected as esters, for example 2,2,2-trichloroethyl and benzyl. These protecting groups are readily cleaved by standard methods when desired.
Sulfoxides and sulfones of Formula 1, wherein n is 1 or 2, are prepared by oxidation of the corresponding sulfides with one or two equivalents of an oxidizing agent such as peracetic acid or meta-chloroperbenzoic acid.
The following detailed examples further illustrate the synthesis of typical invention compounds of Formula I. In the examples where the compound of the example is characterized by elemental analysis of, for illustration, carbon, hydrogen, and nitrogen, the term xe2x80x9cC,H,Nxe2x80x9d means the percents found of carbon, hydrogen, and nitrogen were within xc2x10.4% of their respective theoretical values for the molecular formula recited. The examples are representative only and are not to be construed as limiting the invention in any respect.
All references cited herein are incorporated by reference.